This application is based on German Application DE 100 11 403.2, filed Mar. 9, 2000, which disclosure is incorporated herein by reference.
This invention relates to an improved process for the production of alpha-tocopherol acetate by condensation of trimethylhydroquinone and isophytol in the presence of a catalyst system of a zinc halide and an aqueous Brxc3x8nsted acid and optionally an elemental metal as a third component, wherein the reaction is performed in a polar, protic solvent extractable or miscible with water, preferably acetic acid. After the condensation to yield alpha-tocopherol (xcex1-tocopherol), a phase separation is performed to separate an acetic, aqueous catalyst phase and the resultant product solution separated from water is then esterified at moderate temperatures with an acylating agent, in the presence of the remaining catalyst components, Lewis acid/protonic acid, present in the product phase, and the solution of the catalysts obtained after working up by aqueous extraction after condensation, and acylation is regenerated by suitable methods and returned to the reaction as an acetic catalyst solution. 
TMHQ=trimethylhydroquinone
Ac2O=acetic anhydride
AcOH=acetic acid
LM=solvent
X=halide, hydroxide, oxide
Y=anion of a Brxc3x8nsted acid.
xcex1-Tocopherol and the derivatives thereof are of significance as feed additives, antioxidants, circulatory stimulants, agents for reducing cell aging and for associated applications. Pulverulent formulations of xcex1-tocopherol acetate (vitamin E acetate) with a suitable silica are commercially known for feed additive applications.
The processes which have primarily been described in the prior art are for the production of xcex1-DL-tocopherol, i.e. the unesterified, non-storage-stable, photosensitive form of vitamin E. According to these processes, xcex1-tocopherol is initially produced by condensation of trimethylhydroquinone with isophytol with condensation of water, and is esterified in a separate step with stoichiometric quantities of an acylating agent to yield vitamin E acetate. This method is illustrated in the following reaction scheme: 
According to this prior art, the starting material is generally trimethylhydroquinone (TMHQ), which is reacted with isophytol using various catalyst systems. (U.S. Pat. No. 2,411,969, Hoffmann LaRoche; DE 3 203 487, BASF; U.S. Pat. No. 3,708,505, Diamond Shamrock, U.S. Pat. No. 4,239,691, Eastman Kodak; as well as DE-OS 42 43 464. U.S. Pat. No. 5,523,420, DE-OS 4243464, EP 0 694 541, and DE 196 03 142). The catalysts used for the reaction are generally combinations of Lewis acids, in particular zinc halides, and protonic acids, in particular hydrochloric acid or hydrobromic acid. A mixture of zinc chloride and gaseous hydrogen chloride is advantageously used as a conventional condensation catalyst system, wherein the water arising during the reaction is removed with the solvent by azeotropic distillation or as aqueous acid by distillation. Particularly good yields are achieved, according to EP 0 100 471 and DE 26 06 830 by adding an amine or quaternary ammonium salt as a third catalyst component. EP 0 850 937 A1 also describes the additional use of an amine, in particular tridecylamine (TDAxc3x97HCl), which, in its protonated state, may also assume the form of a quaternary ammonium salt.
Once the reaction is complete, the product must then be acetylated in order to obtain the storage-stable vitamin E acetate usual in commerce.
One disadvantage of this process, which is highly economic with regard to the yields achieved, is the issue of wastewater caused by the use and extractive separation of large quantities of zinc chloride. The catalyst components are conventionally extracted after the condensation with water or with a mixture of water and methanol. In this manner, it is possible to remove both the mixture of protonic acid/Lewis acid and the phase transfer catalyst from the crude tocopherol phase but, after such working up, the crude tocopherol phase may no longer be acylated at moderate temperatures, as the presence of a catalyst is required for mild, selective acylation with acetic anhydride.
In the stated patent literature, the acylation with acetic anhydride is either performed at elevated temperatures of  greater than 100xc2x0 C., or, alternatively, a catalyst is added again. In this connection, both organic bases and Lewis or protonic acids have been described as catalysts for acylating the crude tocopherol. Once the reaction is complete, the catalyst and the acetic acid formed must be separated by extraction with water and a suitable organic extracting agent. The process accordingly comprises in total two complex extraction steps, if esterification is to be performed at moderate temperatures. If the subsequent acetylation is performed purely thermally in the presence of a catalyst by refluxing with acetic anhydride, a corresponding energy input is required.
It is not possible simply to recycle these aqueous zinc halide solutions arising after extraction because, in the case of condensation of TMHQ with isophytol, water, which deactivates the catalyst solution, is also formed during the reaction, in addition to the water required for extraction (c.f. Bull. Chem. Soc. Jpn., 68, (1995), pp. 3569 et seq. and Bull. Chem. Soc. Jpn., 69, (1996), p. 137, left hand column). Attempts to recycle the zinc halide phase extracted with water (approx. 20-60 wt. % ZnCl2) and to reuse it for condensation, result in a reduction in reaction yield and poorer product quality. Evaporating this aqueous catalyst solution to regenerate pulverulent zinc halide involves complex solids handling and is not economic.
In EP 0 850 937 A1, Baldenius et al., the reaction is performed in a solvent which is immiscible or only slightly miscible with water, the catalyst phase is extracted with water after the reaction and, once the aqueous phase has been concentrated to approx. 60%-90%, the resultant catalyst solution is returned to the reaction at 20xc2x0 C.-200xc2x0 C. The disadvantage of this process is the fact that the zinc halide mixture assumes mash form at room temperature and may thus only be conveyed by special pumps designed for this purpose. In order to obtain the catalyst in liquid form, the mash must be heated to an appropriate temperature, which also entails considerable costs.
It is moreover necessary in this process to introduce the protonic acid, preferably hydrochloric acid, as a pure substance in gaseous form during the reaction. The water entering the reaction system due to the recycling of the catalyst mash and the water arising during the reaction are continuously removed during the reaction by azeotropic distillation. It should be noted that, once 1.5 mol of H2O/mol of ZnCl2 have been introduced, azeotropic removal of water may not occur. Larger quantities of water, however, deactivate the catalyst completely.
Another considerable disadvantage is the fact that the acylation catalyst is also removed from the organic phase during aqueous extraction of the catalyst solution. When this process is used, there is no option but either to add fresh catalyst in an additional step or alternatively to perform acylation thermally, which is costly in terms of energy. This disadvantage gave rise to the object to be achieved by the invention of providing a catalyst/solvent matrix which permits both the condensation and the post-acetylation to be performed at moderate temperatures without the necessity of costly addition of fresh catalyst after the condensation.
The selection of the solvent is of particular significance because the condensation solvent also predetermines the subsequent working up and ultimately the catalyst recycling medium.
Using solvents containing esters gives rise to a further difficulty, due to the presence of water during the reaction, in particular if it is economically essential to recycle the catalyst in the form of an aqueous solution. The concentration of water and the temperature required for condensation and ultimately the selection of the ester determine the rate of saponification. Esters of short chain alcohols, in particular, exhibit a strong tendency to saponify and are thus not suitable, readily recyclable solvents for the condensation reaction. In this manner, the ester used as a solvent gives rise to the organic acids and alcohols, which must be removed from the product in an elaborate separation process or which accumulate when the solvent is returned in the recirculation process.
With the exception of the stated literature, the described processes make no mention of the working up of the catalyst solutions used in the reaction.
The object of the invention is to provide an improved process for the production of xcex1-DL-tocopherol esters and to regenerate the catalyst phase obtained in the reaction after working up in such a manner that it may straightforwardly be returned to the reaction without any reduction in catalytic activity. In particular, the object of the invention is to provide a process which permits the active catalyst solution to be recycled in an easily handleable, readily apportionable liquid form, reuse of the catalyst solution without resulting in any reduction in yield or impairment of product quality.
A further object of the invention is to provide a process which permits both the condensation and the reaction with acetic anhydride required for esterification of vitamin E formed xe2x80x9cin situxe2x80x9d to yield vitamin E acetate to be performed at moderate temperature, without requiring repeated apportioning of the catalyst before the condensation and before the post-acetylation and simultaneously avoiding thermal post-acetylation.
In the present invention, moderate temperatures should be understood as temperatures below 100xc2x0 C.
Another object of the invention is, in particular, to provide a process in which both, the reaction and the acetylation with acetic anhydride proceed at moderate temperature, in which both the reaction and the subsequent acetylation proceed using the same catalyst system and in which the catalyst may be recycled in the form of an acetic solution containing water, which is readily handleable and pumpable as a liquid at room temperature, (approximately 25xc2x0 C.) without there being any loss in catalytic activity on repeated recycling.
The problems described above are solved by using a catalyst system comprising an aqueous hydrohalic acid, a zinc halide and optionally an elemental metal, in particular zinc, with acetic acid being used as solvent. Performing the highly selective reaction in acetic acid makes it possible, once the condensation has been performed, to separate the water of reaction together with the majority of the condensation catalyst as an acetic phase from the organic phase containing the product by simple phase separation. The active catalyst components remain in the organic phase in a sufficient concentration for the subsequent acetylation with an acylating agent, in particular acetic anhydride, to be performed efficiently and selectively at moderate temperatures. This allows the same catalyst system to be used without additional apportioning of a catalyst both for condensation and for acylation and simultaneously permits the acylation to be performed at moderate temperatures of between 0xc2x0 C. and 60xc2x0 C. Efficient separation of water in the acetic catalyst phase (catalyst phase I and II) means that the quantity of acetic anhydride required to produce the vitamin E acetate may be reduced, as the acylating agent is consumed stoichiometrically in the presence of water.
In this connection, using an organic carboxylic acid, in particular acetic acid, as solvent allows vitamin E acetate yields of  greater than 96%, before distillation to be achieved, wherein after the reaction, without the presence of the acylating agent, not inconsiderable quantities of vitamin E acetate are already present, in addition to the main product vitamin E. The presence of the main product may be explained by xe2x80x9cin situxe2x80x9d esterification between vitamin E and acetic acid with formation of water which occurs in the presence of the condensation catalyst.
Using acetic acid as the preferred solvent and extracting agent for the catalyst solution after condensation allows the catalyst solution to be recycled in the form of a readily handleable, aqueous acetic solution, which may be regenerated by simple distillation of acetic acid and water in such a manner that none of the catalytically active components are lost with the distillate. The resultant catalyst solution may be returned to the reaction without loss of activity. Due to the phase separation of the tocopherol phase performed after condensation, which gives rise to the aqueous, acetic catalyst phase, it is possible, without adding further extracting agents and water, to obtain a crude tocopherol phase which exhibits a sufficient concentration of the catalyst components to ensure acylation at moderate temperatures, in particular between 20xc2x0 C. and 40xc2x0 C. Handling and the complexity of the plant for apportioning and pumping the catalyst solution are furthermore substantially simplified.
The majority of the catalyst may be separated after the condensation reaction from the vitamin E/vitamin E acetate phase by simple phase separation of the acetic phase (catalyst phase I), wherein an adequate catalyst concentration still remains in the organic phase in order to permit gentle, highly selective post-acetylation at moderate temperatures. After the acetylation, catalyst residues are removed from the vitamin E acetate phase by aqueous extraction and the resultant aqueous catalyst phase (catalyst phase II) is combined with the catalyst phase I obtained after condensation. These catalyst phases are most simply worked up by separation by distillation of a mixture of acetic acid and water without the active catalyst components being entrained in the distillate. An acetic, aqueous concentrated catalyst solution (recycled catalyst solution III) remains, which may be reused for the condensation.
This catalyst solution is also liquid at room temperature and, at moderate temperatures, constitutes a readily handleable and apportionable formulation of the active catalyst.
The invention relates to a process for the production of xcex1-tocopherol acetate by condensation of TMHQ and a phytol derivative, in particular isophytol (IP), at moderate temperatures in the presence of a catalyst system including a zinc halide and a protonic acid and optionally an elemental metal, in particular zinc, in acetic acid as solvent. After the condensation reaction, the mixture of tocopherol/tocopherol acetate obtained after condensation is post-acetylated at moderate temperatures, in the presence of the condensation catalyst, which remains in the organic phase in sufficient concentration after separation of the acetic catalyst phase after condensation, with an aqueous, acetic catalyst solution being regenerated and recirculated. The zinc halide catalyst used preferably is selected from chlorides and bromides, as well as mixtures of these components. The basic chlorides and bromides of zinc, i.e. the corresponding oxy- and hydroxyhalides, also constitute active catalysts for the process according to the invention.
The condensation of the aromatic structural unit TMHQ with IP in the presence of a catalyst system comprising ZnX2 and HY (X=halide, hydroxide, oxide; Y=anion of a Brxc3x8nsted acid), and, optionally, an elemental metal, in particular zinc, added as a third catalyst component proceeds at good yields if the reaction is generally performed in a protic solvent extractable or miscible with water, preferably acetic acid, and the catalyst solution used for the condensation and subsequent acetylation is introduced into the reaction in the form of an aqueous, acetic solution of ZnX2 and HY. The catalyst solution typically contains a zinc halide content of approx. 50 wt %-90 wt. %, 1 wt. %-10 wt. % of HY, 1 wt. %-30 wt. % of water and 1 wt. %-30 wt. % of acetic acid. The molar ratio between the active zinc halide component and water is approx. 1:4, the molar ratio of zinc halide to acetic acid being between 1:10 and 10:1.
The reaction of the components used as educt proceeds in excellent yields in acetic acid. In comparison with the esters conventionally used as solvent for the condensation, acetic acid has the advantages that a) it is inert under the reaction conditions, whereas corresponding conventional esters have a tendency to hydrolyze in the presence of the acid catalysts and water; b) that a mixture of vitamin E and vitamin E acetate is already contained at the condensation stage, such that the quantity of acylating agent may be reduced in the subsequent post-acetylation, c) that aqueous acetic acid is suitable for extracting the acid catalyst and for removing the water of condensation with the catalyst phase I; and d) that acetic acid may simultaneously be used as a solvent for the reaction and as a solvent medium for the active catalyst system. Even when the regenerated catalyst phase is continuously recycled with sub-stoichiometric replenishment of component HY, no loss of catalytic activity is observed, which is in turn manifested as constantly high selectivities and yields.
When the process is performed discontinuously, the acetic acid used as solvent may be added fresh for each batch. In a preferred embodiment, the acetic acid, obtained in a first batch as a secondary product upon acetylation with acetic anhydride, is used as the solvent. The acetic acid concentration relative to the introduced TMHQ may amount to approximately 10 wt. %-300 wt. %, wherein the best results are conventionally achieved at 50 wt. % to 150 wt. % of acetic acid relative to TMHQ.
The quantity of water may be varied within wide ranges and, in order to achieve good results, is generally adjusted to a concentration in the reaction mixture of 10xe2x88x922-400 mol % relative to TMHQ, wherein a molar ratio of TMHQ:water of between 4 and 0.5 (400 mol % to 25 mol %) is preferably established. The quantity of water may be obtained by adding together the concentration of water which is introduced into the reaction in recycled catalyst solution III and the freshly replenished aqueous HY (catalyst/protonic acid). The concentration of water in the reaction mixture is substantially determined by the water content of the recycled catalyst phase III.
The condensation reaction is performed in the presence of the catalyst components ZnX2/HY and, optionally an elemental metal, in acetic acid as solvent at temperatures of between 0xc2x0 C. and 150xc2x0 C., wherein the best results are achieved within a temperature range of from 40xc2x0 C.-120xc2x0 C. The subsequent acetylation is performed in the presence of the catalyst components ZnX2/HY and optionally an elemental metal at temperatures of between 0xc2x0 C. and 100xc2x0 C., wherein the best results are achieved betweem 0xc2x0 C. and 40xc2x0 C.
According to the known patent literature, suitable Lewis acids are zinc salts, in particular halides such as zinc chloride and zinc bromide, wherein this terminology also includes the corresponding hydroxides arising under reaction conditions. The quantities of Lewis acids used relative to the introduced TMHQ are 10 mol %-200 mol %, in particular 20 mol %-50 mol %. When recycling the regenerated catalyst solutions, the Lewis acid concentration is substantially established by the Lewis acid content of the aqueous, acetic recycle solution.
The Lewis acid does not need to be introduced into the reaction as a purchased component, but may instead be produced xe2x80x9cin situxe2x80x9d by mixing appropriate quantities of hydrohalic acid with the corresponding metal, in particular zinc. Once the catalyst solution has been regenerated, virtually all the corresponding zinc halide may be detected again, any missing quantities being made up by replenishment of the elemental metal and an aqueous hydrohalic acid up to the desired concentration.
According to the patent literature, protonic acids which may be used are mineral acids, in particular hydrohalic acids in concentrated form or in the form of the aqueous solutions thereof. Good results are in particular achieved when hydrogen chloride and hydrogen bromide are used, in particular, in the form of concentrated aqueous solutions thereof. Sulfuric acids, sulfuric acid/SO3 mixtures with various SO3 concentrations and superacids with an H0 value of less than or equal to xe2x88x9211.9, such as for example perfluoroalkanoic acids, or mixtures of boric acid and oxalic acid may also be used as acids. The quantities of protonic acids used relative to the introduced TMHQ are 0.01 mol %-100 mol %, in particular 5 mol %-50 mol %. It is preferred to use concentrated solutions of hydrochloric acid and hydrogen bromide.
When recycling the regenerated catalyst solutions, the protonic acid concentration is substantially established by the protonic acid content of the aqueous, acetic recycle solution.
The sequence of addition of educt and catalyst is, in principle, immaterial (this does not apply to isophytol, which is added finally to the mixture of the other components) and is understood by way of example in the following description.